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romidepsin

( ROE-mi-DEP sin )
Funding:
New Drug Funding Program
  • Romidepsin - Relapsed or Refractory Peripheral T-Cell Lymphoma
Other Name(s): Istodax® (Celgene)
Appearance: Clear, colourless solution mixed into larger bags of fluids
A - Drug Name

romidepsin

SYNONYM(S):   FK228; FR901228

COMMON TRADE NAME(S):   Istodax® (Celgene)

 
B - Mechanism of Action and Pharmacokinetics

Romidepsin, initially isolated from Chromobacterium violaceum, is a bicyclic peptide inhibitor of Class I histone deacetylases. Accumulation of acetylated histones induces cell cycle arrest and apoptosis in some cancer cell lines, although the exact mechanism of its anticancer effect is not clear. Romidepsin is a prodrug and requires reduction of disulfide bonds for activation.



Absorption

Exhibited linear pharmacokinetics over the recommended dosing range.  No accumulation was observed after repeat dosing.

Peak plasma levels 3 hours (median)

Distribution

Rapid distribution into many tissue and organ systems.  Accumulates into human hepatocytes via an unknown uptake mechanism.

PPB 92-94%, mainly to alpha-1 acid glycoprotein
Cross blood brain barrier? Very low
Metabolism
Main enzymes involved mainly CYP 3A4, minor with CYP3A5, 1A1, 2B6, 2C19.  Also a substrate of Pgp and MRP1.
Active metabolites
Inactive metabolites approximately 30, each < 5% of total dose
Elimination

Multiphasic elimination; mainly eliminated through bile with excretion into feces.  Age, gender and race did not appear to affect the pharmacokinetics of romidepsin.

Half-life 3.7 hours
Feces 96%
Urine <20%, with <5% parent drug
 
C - Indications and Status
Health Canada Conditional Approvals
(pending the result of studies to verify the drug’s clinical benefit. Patients should be advised of the nature of the marketing authorization granted.)

For the treatment of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL) who are not eligible for transplant and have received at least one prior systemic therapy.

Note:

Approval in peripheral T-cell lymphoma was based on response rates; improvement in overall or progression-free survival has not been demonstrated.



 
D - Adverse Effects

Emetogenic Potential:  

Low

Extravasation Potential:   Minimal

The following adverse effects were reported from the pivotal single arm clinical trial.

ORGAN SITE SIDE EFFECT* (%) ONSET**
Cardiovascular Hypotension (8%) I  E
QT interval prolonged (rare) E
Tachycardia (10%) E
Venous thromboembolism (4%) E
Dermatological Rash (9%) E
Gastrointestinal Abdominal pain (14%) E
Anorexia, weight loss (28%) E
Constipation (30%) E
Diarrhea (36%) E
Dyspepsia (8%) E
Mucositis (11%) E
Nausea, vomiting (59%) I
General Edema (10%) E
Fatigue (55%) (severe 8%) E
Hematological Myelosuppression ± infection, bleeding (29%) (grade 3 or 4, including opportunistic infections/ viral reactivation) E
Hepatobiliary ↑ LFTs (29%) (severe 2%) E
Hypersensitivity Hypersensitivity (rare) I
Metabolic / Endocrine Abnormal electrolyte(s) (11%) (especially hypomagnesemia, hypokalemia) E
Tumor lysis syndrome (2%) I
Musculoskeletal Musculoskeletal pain (9%) E
Nervous System Anxiety (7%) E
Depression (5%) D
Dizziness (8%) E
Dysgeusia (21%) E
Headache (15%) E
Insomnia (7%) E
Respiratory Cough, dyspnea (18%) E


* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare" may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal reports.
Dose-limiting side effects are underlined.

** I = immediate (onset in hours to days)     E = early (days to weeks)
D = delayed (weeks to months)      L = late (months to years)

The most common side effects for romidepsin include nausea/vomiting , fatigue, myelosuppression ± infection/bleeding, diarrhea, constipation, ↑ LFTs, anorexia/weight loss, dysgeusia, cough/dyspnea and headache.

Gastrointestinal adverse effects such as nausea, vomiting, constipation and diarrhea were generally mild to moderate.

Serious or fatal infections have been observed during treatment and within 30 days after treatment. Patients with a history of bone marrow involvement or prior treatment with monoclonal antibodies directed against lymphocyte antigens may have high risk of infections.  Viral reactivation (hepatitis B, CMV, EBV) has been described; consider prophylaxis and monitoring patient.

 

 
E - Dosing

Refer to protocol by which patient is being treated. Plasma potassium and magnesium levels should be within normal range before each romidepsin administration; do not treat if QTc > 480 ms. Patients at risk of tumour lysis syndrome should have appropriate prophylaxis and be monitored closely.



Adults:

Dose levels:  Do not re-escalate reduced doses.

Dose level Dose (On days 1, 8, 15)
Starting dose 14 mg/m2
First reduction 10 mg/m2
Second reduction Discontinue

Q 28 day cycle: 


Intravenous: 14 mg/m² Days 1, 8, 15

Dosage with Toxicity:

Dose modifications:

Worst Counts (x109/L) / Toxicity
Action
Grade 2 or 3 non-hematological/ organ
Hold*, restart at same dose level
If grade 3 recurs, hold* then ↓ 1 dose level.
If grade 3 recurs after dose reduction, discontinue.
 
Grade 4 non-hematological/ organ
Hold*, restart by ↓ 1 dose level
If grade 3 or 4 recurs after dose reduction, discontinue.
 
Grade 3 or 4 ANC or platelets
Hold*, restart at same dose level
 
Grade 4 febrile neutropenia or thrombocytopenia requiring platelet transfusion Hold*, restart by ↓ 1 dose level
 *Do not retreat until platelets ≥ 75 x 109/L, ANC ≥ 1.5 x 109/L, non-hematological/organ toxicities recover to  ≤ grade 1 or baseline.


Dosage with Hepatic Impairment:

Not formally studied.  Population pharmacokinetic analysis suggested the following:

Bilirubin   AST Dose
≤ ULN and > ULN No change (no significant pharmacokinetic differences)
1 to 1.5 x ULN and any No change (no significant pharmacokinetic differences)
>1.5 to 3 and any Caution (no data)
> 3 x ULN and any                                Caution (no data)

 

 



Dosage with Renal Impairment:

Not formally studied. Population pharmacokinetic analysis suggested that renal impairment was not expected to affect drug exposure significantly:

Renal Impairment Dose
Mild (> 50-80) No change
Moderate (30-50) No change
Severe (< 30) No change
ESRD Caution (no data)


Dosage in the elderly:

No overall safety and efficacy differences were observed between elderly and younger patients; however, elderly patients may require dose modifications due to increased risk of toxicity.



Children:

Safety and efficacy have not been established in patients < 18 years of age.



 
F - Administration Guidelines
  • Reconstitute romidepsin using the supplied diluent. Refer to the product monograph for instructions.
  • Add the required dose into 500 mL 0.9% Sodium Chloride (NS).
  • Infuse IV over 4 hours.
  • Missed doses should be administered as soon as possible, unless it is within 5 days of the next scheduled dose
  • Diluted solution is compatible with PVC, ethylene vinyl acetate (EVA) polyethylene (PE) infusion bags as well as glass bottles
  • Store unopened vial and diluent together at room temperature (15 to 30oC)
  • The manufacturer recommends that the reconstituted drug is stable for at least 8 hours when stored at room temperature.  After dilution with 0.9% sodium chloride solution (NS), it is stable up to 24 hours at room temperature
 
G - Special Precautions
Contraindications:

  • Patients who have hypersensitivity to this drug or any of its components
  • Baseline QT prolongation > 480 ms
  • Patients with congenital long QT syndrome
  • Abnormal plasma magnesium or potassium levels

Other Warnings/Precautions:

  • Patients with a significant cardiac history were excluded from clinical trials; exercise extreme caution in these patients
  • Use with caution in patients who are at risk of experiencing torsade de points or QT prolongation, including female patients, age ≥ 65 years, congenital long QT syndrome, cardiac disease, history of arrhythmias, electrolyte disturbances, bradycardia, acute neurological events, diabetes, on concomitant antiarrhythmics or drugs that prolong QT, or autonomic neuropathy
  • Use with caution in patients with bulky disease due to the risk of tumour lysis syndrome
  • Use with caution in patients with compromised bone marrow (disease, or heavily pretreated) due to the risk of infection


Other Drug Properties:

  • Carcinogenicity: Unknown

Pregnancy and Lactation:
  • Fetotoxicity: Yes
    Romidepsin is not recommended for use in pregnancy.  Adequate contraception should be used by both sexes during treatment, and for at least 8 weeks after the last dose.  Estrogen-containing contraceptives should not be used (refer to interactions).  Male patients, including vasectomized males, should use condoms with spermicide.
  • Embryotoxicity: Yes
  • Teratogenicity: Yes
  • Mutagenicity: No
  • Clastogenicity: No
  • Lactation: Not recommended
    It is not known whether romidepsin is excreted into human milk.
  • Fertility effects: Yes
    These effects may be irreversible.
 
H - Interactions

Romidepsin does not significantly inhibit or induce CYP450 substrates, but is susceptible to drug interactions from CYP3A4 inhibitors/inducers.

AGENT EFFECT MECHANISM MANAGEMENT
CYP3A4 inhibitors (i.e. ketoconazole, clarithromycin, ritonavir, fruit or juice from grapefruit, Seville oranges or starfruit) ↑ romidepsin concentration and/or toxicity ↓ metabolism of romidepsin Avoid use with strong inhibitors. Caution with moderate inhibitors; monitor for toxicity
CYP3A4 inducers (i.e. phenytoin, rifampin, dexamethasone, carbamazepine, phenobarbital, St. John’s Wort, etc) ↓ romidepsin concentration/efficacy (theoretical), ↑ romidepsin exposure observed with rifampin ↑ metabolism of romidepsin; rifampin may inhibit hepatic uptake that limits romidepsin access to induced CYP3A4 Avoid strong CYP3A4 inducers
Coumarin derivatives ↑ PT and INR observed Unknown Caution; monitor PT and INR closely
Estrogen containing contraceptives ↓ effectiveness of estrogen-containing contraceptives Competition with binding to the estrogen receptors Caution; use alternate non-estrogen contraception (e.g. condoms, IUD); monitor for estrogen deficiency in patients on hormone replacement therapy
P-glycoprotein inhibitors (i.e. quinidine, verapamil, cyclosporine) ↑ Romidepsin concentration and/or toxicity ↓ Romidepsin elimination Caution
Drugs that may prolong QT (i.e. amiodarone, procainamide, sotalol, venlafaxine, amitriptyline, sunitinib, methadone, chloroquine, clarithromycin, haloperidol, fluconazole, moxifloxacin, domperidone, ondansetron, etc) ↑ QT prolongation effect Additive Caution; monitor patient closely
Drugs that disrupt electrolyte levels (i.e. loop/thiazide diuretics, laxatives, amphotericin B, high dose corticosteroids) ↑ risk of QT prolongation Electrolyte disturbance Avoid if possible
 
I - Recommended Clinical Monitoring

Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.

Recommended Clinical Monitoring

Monitor Type Monitor Frequency

Electrolytes, including potassium and magnesium

baseline, before each cycle and as clinically indicated
INR and PT for patients taking warfarin or its derivatives baseline and regular
CBC baseline and before each treatment (at minimum)

ECG; baseline; baseline and periodic for patients at risk of QT prolongation

baseline and as clinically indicated

Clinical toxicity assessment for infection, bleeding, thromboembolism, fatigue, GI effects, hypersensitivity, tumour lysis syndrome

at each visit

Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version



 
J - Supplementary Public Funding

New Drug Funding Program (

NDFP Website

)
  • Romidepsin - Relapsed or Refractory Peripheral T-Cell Lymphoma

 
K - References

Coiffier B, Pro B, Prince HM, et al. Results from a pivotal, open-label, phase II study of romidepsin in relapsed or refractory peripheral T-cell lymphoma after prior systemic therapy. J Clin Oncol 2012 Feb 20;30(6):631-6.

Product Monograph: Istodax® (romidepsin). Celgene Inc., December 13, 2016.

Yang LPH. Romidepsin: in the treatment of T-cell lymphoma. Drugs 2011;71(11):1469-80.


November 2017 added reference to product monograph in administration section

 
L - Disclaimer

Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.

The information set out in the drug monographs, regimen monographs, appendices and symptom management information (for health professionals) contained in the Drug Formulary (the "Formulary") is intended for healthcare providers and is to be used for informational purposes only. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects of a particular drug, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for a given condition. The information in the Formulary is not intended to constitute or be a substitute for medical advice and should not be relied upon in any such regard. All uses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the information provided in the Formulary.

The format and content of the drug monographs, regimen monographs, appendices and symptom management information contained in the Formulary will change as they are reviewed and revised on a periodic basis. The date of last revision will be visible on each page of the monograph and regimen. Since standards of usage are constantly evolving, it is advised that the Formulary not be used as the sole source of information. It is strongly recommended that original references or product monograph be consulted prior to using a chemotherapy regimen for the first time.

Some Formulary documents, such as the medication information sheets, regimen information sheets and symptom management information (for patients), are intended for patients. Patients should always consult with their healthcare provider if they have questions regarding any information set out in the Formulary documents.

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